The treatment of malaria involves two major approaches: supportive measures as well as the use of specific antimalarial drugs. The objective of supportive measures is to deal with discomforting malaria symptoms such as fever, aches and pains, nausea and vomiting, dehydration and loss of appetite. Drugs such as analgesics, antipyretics, anti-emetics, hematinics and multivitamins are often used in conjunction with specific antimalarials. Giving analgesics controls fever and muscular pains. In case of severe dehydration, intravenous fluids are indicated and blood transfusions may be given when there is severe anemia. For mild anemia, iron and folic acid therapy should be initiated. Cellular metabolism is assisted by the administration of vitamin B-complex and secondary infections can be controlled by the use of appropriate antibiotics (Adepoju-Bello and Ogbeche, 2003). Severe and active malaria infection with P.falciparum is a medical emergency requiring hospitalization. But infections involving P.vivax, P.ovale or P.malariae can often be treated on an outpatient basis. Successful chemotherapy of malaria depends on the exploitation of the biochemical differences of the parasite and the host. Based on mechanism of action, antimalarials could be divided into two major classes. The first class includes the cinchona alkaloids, the 8- and 4-aminoquinolones and the acridines. They act either by inhibiting
protein synthesis or the enzyme systems involved in the biosynthesis of precursors of DNA itself (through DNA replication and RNA transcription) Thus blocking the synthesis of DNA and RNA of plasmodia by inhibiting DNA and RNA polymerase. These drugs position or intercalates between base pairs of adjacent strains of DNA, causing them to begin unwinding.
The second class includes the dihydrofolate reductase inhibitors (DHFR). Trimethoprim, proguanil, cycloguanil and pyrimethamine are in this class. It is known that the malaria protozoa cannot convert folic acid to tetrahydrofolic acid (FAH4) but can convert dihydrofolic acid (FAH2) to FAH4. The dihydrofolate reductase inhibitors owe their antimalarial activity to selective inhibition of dihydrofolate reductase which converts FAH2 to FAH4 of the parasite. The inhibition interferes with plasmodia biosynthesis leading to formation of purine and pyrimidines bases and eventually of DNA. The drug is selective in action because it binds more tightly to the dihydrofolate reductase of plasmodia than to the same enzyme of the host. Thus any agent that can inhibit the malaria protozoa’s biosynthesis of FAH2 or can selectively inhibit the protozoa’s dihydrofolate reductase can inhibit the growth of the protozoa and eventually kill it (Adepoju-Bello and Ogbeche, 2003).
Mefloquin does not bind to DNA. It is possible that its potent antimalarial activity may be from increasing the protozoa’s intracellular PH. The sulphonamides and sulphones act as antimalarials by competitively inhibiting dihydroptorate synthase, the enzyme that catalyses the incorporation of para-amino benzoic acid (PABA) into dihydropteroic acid. The interference of sulphonamides in this reaction results in the protozoa’s death.
There are several families of drugs employed in the treatment of malaria. The drugs are grouped according to the objective of the clinician. Some drugs are for prophylaxis while others are for suppressive therapy. Then we have the ones for clinical cure and radical cure. The process by which the infection is before the development of obvious symptoms is referred to as causal prophylaxis. A causal prophylactic agent acts on the exoerythrocytic stage of the plasmodia. Eradicating the parasite before they release the merozoites into the blood stream prevents transmission to new insect hosts and thus continuation of the life cycle. Falciparum malaria is the most susceptible to prophylactic treatment. Pyrimethamine and primaquine have marked prophylactic properties, but the latter is rarely used for this purpose because of its serious side effects (Olaniyi, 1999).
Proguanil is an effective prophylactic agent against P. falciparum malaria but is not fully effective against vivax malaria. It acts against the exoerythrocytic stages, preventing the development of merozoites, but has no effect against gametocytes. It is not used in acute malaria attacks due to its slow onset of action, even though it is effective against the asexual stage of all species. Proguanil hydrochloride (paludrine) is administered to non immune individuals in a prophylactic dose of 100 mg per day orally. Adequate protection is given to semi-immune individuals by a weekly dose of 330mg. When used to treat acute attacks of vivax malaria, it is administered in an initial dose of 300-600mg followed by 300mg daily for five weeks (Adepoju-Bello and Ogbeche, 2003)
In terms of suppressive therapy, the drugs employed act on erythrocytic stage of the parasite. They do not eradicate the infection because the exoerythrocytic stage is unaffected but suppress the symptoms of malaria. However a cure may be achieved by the continuous use of a suppressive agent. For example if pyrimethamine is administered for 10 weeks after leaving endemic area, it can eradicate vivax malaria. When suppressive agents are taken for shorter periods however, and withdrawn, symptoms of malaria may return as a result of the exoerythrocytic stage persisting in the liver (Adepoju-Bello and Ogbeche, 2003).
Pyrimethamine is used as a prophylactic and a suppressive agent. It is considerably more potent than proguanil as it acts directly and has a longer half-life. It acts against the asexual forms of the parasite in the blood and also subsequently prevents the development of the zygote in the mosquito. Also pyrimethamine has shown considerable promise when combined with sulphadoxine in the treatment of chloroquine resistant falciparum malaria (Olaniyi, 1989).
The group of drugs used in the clinical cure of malaria act on the asexual erythrocytic stages and prevent the development of the schizonts. Chloroquine and amodiaquine both derivatives of 4-aminoquinoline are in this group (Olaniyi, 1989). They act against both falciparum and vivax infections. Until recently, chloroquine has been the antimalaria drug of choice because it is very cheap, available and very effective against falciparum and vivax malarial infections. However, resistance of P.falciparum to chloroquine has spread recently from Asia to Africa, making the drug ineffective against the most dangerous strains in many affected regions of the world (White et al., 2004). In those areas where chloroquine is still effective, it remains the first choice. Unfortunately, its resistance is associated with reduced sensitivity to other drugs such as quinine and amodiaquine (Tino et al., 2006). Chloroquine has a rapid onset of action and is therefore used in acute malarial attack, when it relieves symptoms within 24-48 hours (Aguwa, 1996).
Radical cure is effected with primaquine which is a derivative of 8-aminoquinoline. This drug eradicates the exoerythrocytic stage of malaria parasites, but is ineffective against the erythrocytic stages of falciparum pathogen. Primaqine phosphate is administered in conjunction with chloroquine to reduce the risk of developing drug resistance strains. The treatment entails an initial oral 600mg dose of chloroquine base, followed by a further 300mg of chloroquine combined with 45mg of primaquine 6 hours later. This combined dose is then given once a week for 7 weeks (Adepoju-bello and Ogbeche, 2003).
Recently several new drugs have been developed and are now employed in the clinical cure of malaria. Mefloquine which is a quinoline methanol hydrochloride is a blood shizonticide and is effective against drug resistance P.falciparum and P.vivax infections in most tropical countries. Mefloquine resistance has been reported in West and East Africa, Southeast Asia and Thailand (Aguwa, 1996). To deal with this, mefloquine may be combined with artemether or artesunate. This combination improves cure time significantly and reduces resistance (Adepoju-Bello and Ogbeche, 2003). Also, the combination of mefloquine with sulphadoxine and pyrimethamine has been shown to improve compliance (Aguwa, 1996).
Another important drug used for clinical cure is Halofantrine. It is a phenathrne methanol antimalarial drug related to mefloquine and is effective against asexual forms of multi-drug resistant P. falciparum. An oral dose of 500mg every 6 hours is well tolerated and found to be more effective than mefloquine against resistant P.falciparum (Olaniyi, 1989). The administrations of fatty foods have been found to improve the absorption of halophatrine. Treatment failures have been attributed to incomplete absorption of the drug (Adepoju-Bello and Ogbeche, 2003).
The current and most important antimalarial drug is the extracts of the plant Artemesia annua which contain the compound artemesinin or its semi-synthetic derivatives. The advent of artemisinin and its semi-synthetic analogues such as artesunate, artemether, arteather and dihydroatemisinin has added to the antimalarial armamentarium. These compounds have a remarkably rapid onset of action and offer over 90% efficacy rates, but their supply is not meeting demand (Senior, 2005).
In 2007, Bill and Melinda Gates foundation contributed 13.6 million dollars to support research at the University of York to develop fast and high yield strains of artemesia, with researchers predicting an increase in yield of up to 1000% compared to current varieties.
The artemisinin derivatives are very effective in severe falciparum malaria and in multi-drug resistant strains of P. falciparum. A combination of mefloquine and artesunate is effective (Adepoju-Bello and Ogbeche, 2003).
It has been observed that large doses of antimalarial agent are often used to treat cases of malaria due to the frequency of resistant parasites in the area where the drug is used. Propranolol, a drug used in the management of hypertension is currently being investigated because it has been shown to block both plasmodiums’ ability to enter red blood cells and establish infection, as well as parasite replication. A study conducted in December, 2006 by Northwestern University researcher suggested that propranolol may reduce the dosages required for existing drugs to be effective against P. falciparum by 5-10 folds, suggesting a role in combination therapy (Murphy et al., 2006).
It has also been observed that no matter how effective a single agent may be, it will eventually fall a victim of Plasmodia resistance. To avert this fate, the World Health Organization (WHO) since 2001, has recommended that Artemisinin based Combination Therapy (ACT) should be used as first line treatment for uncomplicated malaria in areas experiencing resistance to older medications. Numerous countries including most African nations have adopted the change in their official malaria treatment policies to the WHO recommended ACT policy. However, the cost of an ACT treatment is twenty times as much as older medications. Thus they remain unaffordable in many malaria-endemic countries. Another source of worry in the ACT policy is the possible development of resistance by malaria parasite. This resistance can be produced by the mutation of SERCA, a calcium pump in the endoplasmic reticulum of the parasite (Eckstein-Ludwig et al., 2003).
Currently, the Artemisinin based combination antimalarials in use include Artemether-Lumefantrine, Artesunate-amodiaquine, Artesunate-Mefloquine, and Artesunate-Sulfadoxine/Pyrimethamine. We also have Artesunate-Sulfamethoxypyrezine/pyrimethamine. It has also been observed that concurrent administration of antibiotics like doxycycline with antimalarials has improved clinical therapeutic outcome (Adepoju-Bello and Ogbeche, 2003).
The treatment of patients with complicated severe malaria such as cerebral malaria requires an intensive care. Blood transfusion, correction and maintenance of blood glucose, ventilation and dialysis are often needed. Antimalaria drugs must be given parenterally. Quinine is the drug of choice and it is normally continued until the patient is able to take alternative drugs orally (Adepoju-Bello and Ogbeche, 2003).
The health and economic impact of malaria has spurred researchers to continue the search for better, safer and more cost effective cure for malaria. One of such effort was by a team of French and South-African researchers who announced progress on a new treatment for infected persons. This new drug which they called “G25” cured malaria in test primates by blocking the ability of the parasite to copy itself within the red blood cells of its victims. However, since 2005 they announced their success, there is no information yet as to when this family of drug will become commercially available.
Although effective antimalarial drugs abound in Nigerian markets, it is however a common knowledge in our setting that the disease continues to be a threat to people living in endemic areas who have no proper access to effective drugs. Thus access to pharmacies and health facilities, as well as drug costs are major challenges.
RELATED INFORMATION